The Relevance of G-Quadruplexes for DNA Repair

Abstract

DNA molecules can adopt a variety of alternative structures. Among these structures are G-quadruplex DNA structures (G4s), which support cellular function by affecting transcription, translation, and telomere maintenance. These structures can also induce genome instability by stalling replication, increasing DNA damage, and recombination events. G-quadruplex-driven genome instability is connected to tumorigenesis and other genetic disorders. In recent years, the connection between genome stability, DNA repair and G4 formation was further underlined by the identification of multiple DNA repair proteins and ligands which bind and stabilize said G4 structures to block specific DNA repair pathways. The relevance of G4s for different DNA repair pathways is complex and depends on the repair pathway itself. G4 structures can induce DNA damage and block efficient DNA repair, but they can also support the activity and function of certain repair pathways. In this review, we highlight the roles and consequences of G4 DNA structures for DNA repair initiation, processing, and the efficiency of various DNA repair pathways.

Keywords: G-quadruplex; genome instability; homologous recombination; non-homologous end joining; nucleotide excision repair; translesion synthesis.

Figure 1

Overview of DNA damage-specific repair pathways. DNA repair mechanisms that are discussed in this review are summarized in this illustration: homologous recombination (HR), non-homologous end joining (NHEJ), base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR) and translesion synthesis (TLS). In the inner circle the type of lesion is named and illustrated in the middle circle. In the outer circle major proteins that act during the repair pathway are listed. Figure was created using BioRender.com.

Figure 2

Schematic illustration of canonical DDR. (A) Cartoon of essential steps and key proteins during HR. Relevance and consequences of G4 structures are highlighted in the box. (B) Cartoon of essential steps and key proteins involved in NHEJ. Relevance and consequences of G4s are highlighted in the box. Figure was created using BioRender.com.

Figure 3

Schematic illustration of post-replicative DDR and translesion synthesis. (A) Cartoon of essential steps and proteins during BER. Relevance of G4 formation during initiation and lesion processing are highlighted in the box. (B) Cartoon of essential steps and proteins during NER. Relevance of G4 formation is indicated in the box. (C) Cartoon of essential steps and proteins during MMR. Relevance of G4 formation is indicated in the box. (D) Cartoon of essential steps and proteins during TLS. Relevance of G4 formation during initiation and lesion processing is highlighted in the box. Figure was created using BioRender.com.

Figure 3

Schematic illustration of post-replicative DDR and translesion synthesis. (A) Cartoon of essential steps and proteins during BER. Relevance of G4 formation during initiation and lesion processing are highlighted in the box. (B) Cartoon of essential steps and proteins during NER. Relevance of G4 formation is indicated in the box. (C) Cartoon of essential steps and proteins during MMR. Relevance of G4 formation is indicated in the box. (D) Cartoon of essential steps and proteins during TLS. Relevance of G4 formation during initiation and lesion processing is highlighted in the box. Figure was created using BioRender.com.

Figure 4

Impact of G4s on DNA repair pathways. G4 DNA structures can influence the function of DNA repair mechanisms but can also contribute to genome stability. On the one hand G4 structures positively affect the repair of DNA damages recognized and repaired by NER. On the other hand, G4 structures have a negative impact on the repair efficiency of HR and NHEJ and MMR. BER can be both positively and negatively affected by G4 structures. TLS is not affected by G4 structures as it is able to replicate through these secondary structures to maintain genomic stability. Figure was created using BioRender.com.